This course will prepare the healthcare professional to assess and participate in hyperbilirubinemia treatment in the neonate.
This course will prepare the healthcare professional to assess and participate in hyperbilirubinemia treatment in the neonate.
After the completing this continuing education course, the participant will be able to meet the following objectives:
Jaundice is one of the most common physiologic problems requiring medical attention in the newborn. Jaundice in newborns usually has a different significance and a different medical response than it has in older children and adults. All infants, term or preterm, healthy, or ill, change bilirubin metabolism after birth. These normal transitional changes may lead to physiologic jaundice. Some infants exaggerate normal transitional changes or additional health alterations that result in an accumulation of excess bilirubin or pathologic jaundice.
Jaundice, which occurs in 50 to 60 percent of newborns, is a yellowing of the skin that develops because of indirect bilirubin in the blood. Jaundice can be detected in a well-lit room or in daylight by blanching the skin with finger pressure and comparing the skin's underlying color and subcutaneous tissue. For visible staining of the skin and sclera, a level of at least 5mg/dl is required.1
The head-to-toe progression of jaundice over the body gives a crude estimate of the level of bilirubin. The newborn produces up to 8.5 to 10 mg/kg/day of bilirubin, and production is inversely correlated to gestational age. Normally, an infant can produce 34-35 mg of unconjugated bilirubin from each gram of hemoglobin. Destruction of circulating RBCs accounts for about 75 percent of the bilirubin produced in the healthy term newborn. Catabolism of nonhemoglobin heme, ineffective erythropoiesis, and enterohepatic recirculation or shunting account for 21 to 25 percent of the bilirubin produced in the term and 30 percent in the preterm infant.
Metabolism of bilirubin occurs in the liver and spleen as old red blood cells are broken down. Bilirubin is derived from the catabolism of proteins that contain heme. Quantitatively, the most important bilirubin source is the breakdown of hemoglobin from red blood cells (RBC). Bilirubin is produced after completion of the natural span of the RBC, but ineffective erythropoiesis (formation of RBCs), or premature destruction of blood cells, can increase the production of bilirubin.2 In RBC destruction, the aging or hemolyzed red blood cell membrane ruptures, releasing hemoglobin that is phagocytized by macrophages. The hemoglobin molecule then splits into a heme portion and a globulin portion. Bilirubin is derived from the heme portion of hemoglobin.
Bilirubin metabolism begins when the heme portion of hemoglobin is oxidized into biliverdin by a microsomal enzyme called heme oxygenase. Biliverdin is then catabolized into unconjugated or indirect bilirubin by the enzyme biliverdin reductase. Unconjugated bilirubin in the plasma is released into the circulation, where most are transported to the liver tightly bound to albumin.3 Binding is affected by plasma pH and medications. Only a small amount of unconjugated bilirubin is unbound, or free, within the plasma. Once conjugated bilirubin reaches the liver, it is released from the albumin and transported into liver hepatocytes by ligandin or Y carrier proteins.
Once in the liver, unconjugated bilirubin is conjugated by the hepatic enzyme uridine diphosphoglucuronosyl transferase (UDPGT) in the presence of adequate amounts of glucose and oxygen. UDPGT catalyzes the binding of indirect bilirubin to a simple sugar called glucuronic acid, forming monoglucuronide. Two-thirds of the monoglucuronide undergoes further conjugation by UDPGT, forming diglucuronide. Monoglucuronides and diglucuronides are collectively referred to as bilirubin glucuronides or conjugated bilirubin.3
Carrier proteins then transport conjugated bilirubin into the biliary tree, where it mixes with bile and passes into the intestines for excretion from the body. Once these bilirubin glucuronides reach the intestines, normal bacterial flora converts them into urobilinogen and stercobilinogen, which are excreted into stool and urine. Stercobilinogen contributes to the normal yellow-brown color of stool. A small amount of urobilinogen is reabsorbed back into the circulation through the colon and is eventually excreted in the urine. Conjugated bilirubin can also be hydrolyzed, or deconjugated, by the intestinal B-glucuronidases and reabsorbed back through the enterohepatic circulation.3 This deconjugated bilirubin travels back to the liver, where it undergoes conjugation for a second time.
There are two forms of circulating bilirubin: unconjugated (indirect) and conjugated (direct). Each of these forms of bilirubin possesses unique identifying characteristics4:
|Indirect (Unconjugated) Bilirubin||Direct (Conjugated) Bilirubin|
|The product of hemoglobin metabolism with the reticuloendothelial system||The product of bilirubin metabolism within the liver|
|Cannot be readily excreted in bile or urine; must undergo conjugation in the liver before it can be excreted||Is readily excreted into bile, stool, and urine|
|Most bound to albumin in plasma; a small amount free in the plasma||Only a small amount (<2mg/dl) normally found within the plasma|
|Can be measured only indirectly by subtracting the direct bilirubin level from the total bilirubin level||Can be measured directly in plasma|
Unconjugated bilirubin is a potentially toxic form of bilirubin. Albumin has a finite number of binding sites for bilirubin. Consequently, in the presence of hyperbilirubinemia, more indirect bilirubin circulates in an unbound, or free, state as albumin binding sites become saturated. Because indirect bilirubin is lipid-soluble, it crosses cell membranes, including the skin, the sclera, and the blood-brain barrier when it circulates in an unbound form. Therefore, free indirect bilirubin can potentially accumulate with the brain, where it causes neurotoxic injury to the central nervous system (CNS), resulting in bilirubin encephalopathy or kernicterus.5
Approximately 50 percent of term and 80 percent of preterm infants develop visible jaundice and rising serum total bilirubin levels over the first three to four days of life.6 Physiologic jaundice, or neonatal hyperbilirubinemia, typically presents over the first few days of life. It is defined as a total bilirubin value <13mg/dl or slow-rising total bilirubin level, which increases <0.5mg/dl/hour. For most infants, serum bilirubin's rise reflects a normal physiologic increase in bilirubin levels from the normal fetal hemoglobin breakdown. Physiologic jaundice causes include:
Breastfeeding accounts for most term infants with bilirubin > 12 mg/dl and has two forms: early (breastfeeding-related) and late (breast milk related). Early-onset is seen on day two to four and attributed to feeding practices. It also includes increased enterohepatic circulation, decreased feeding, and fluid intake; therefore, increasing fat metabolism and decreased hepatic function. Breastfed infants excrete less bilirubin in stools.7 Late-onset breast-milk related jaundice has increased bilirubin levels on day four and peak at 10 - 30 mg/dl. The infant is jaundiced from day ten to fifteen for three to twelve weeks. This occurs in 1:100 – 200 infants and is related to the constituents in breast milk.
A rapidly rising total serum bilirubin value – one that increases by >0.5mg/dl/hour within the first 24 hours or that presents after the first week of life, or prolonged jaundice beyond fourteen days in term infants and 21 days in preterm infants is indicative of pathologic causes of hyperbilirubinemia. The most common pathologic causes of indirect hyperbilirubinemia include3:
Direct hyperbilirubinemia is defined as a serum direct bilirubin value >2mg/dl or >15-20 percent of the total serum bilirubin value. Direct hyperbilirubinemia results from pathologic causes that prevent conjugated bilirubin from being excreted from the hepatocytes into the biliary system or the duodenum. For this reason, direct hyperbilirubinemia is a marker indicating the presence of hepatic dysfunction. Any delay in diagnosing and treating direct hyperbilirubinemia can result in progressive liver damage related to retained or refluxed bilirubin within the liver. It has been shown that cholestasis lasting just 30 days can lead to irreversible liver damage. Cholestasis includes conditions in which bile flow is decreased or absent at the level of the hepatocytes or bile ducts; this results in the infant's retaining bile components, including direct bilirubin.8
The list of disorders and diseases associated with direct hyperbilirubinemia is extensive, so making a differential diagnosis can seem impossible. Many of these diseases and disorders are very rare. Some of the most common causes seen in the neonatal intensive care unit (NICU) include:
Although bilirubin is found in stool and amniotic fluid, the major route of elimination of the fetus is through the placenta. All bilirubin found in the cord blood is of the unconjugated variety owing to the effective handling of bilirubin metabolism conjugation and excretion by the maternal liver and gall bladder. The mean cord blood bilirubin concentration is 1.8mg/dl regardless of the infant's gestational age or weight. As bilirubin production exceeds the newborn liver's capacity to conjugate and eliminate it, the plasma level begins to rise rapidly. Jaundice becomes noticeable when the serum concentration reaches three times the normal amount present in the serum.9
In the full-term infant, jaundice becomes apparent within two to four days after birth and lasts until the sixth day, reaching a peak concentration of 6 to 7 mg/dl. The preterm infant has cord blood levels similar to those of the term infant, but peak levels are higher, jaundice lasts longer, and levels peak later at five to seven days. Sixty-three percent of preterm infants achieve levels of 10 to 19 mg/dl, and 22 percent will reach levels > 15 mg/dl. Although the neonatal liver's conjugating mechanisms are reduced during the first few days of life, it possesses the ability to metabolize and excrete two-thirds to three-quarters of the bilirubin circulating throughout the body.
Both total serum bilirubin (TSB) and direct bilirubin (fraction conjugated with glucuronic acid) are commonly measured. In-office instruments are available for TSB measurements but may not be sufficiently accurate in the most important range (over 18 mg/dl). There are several instruments on the market that give transcutaneous bilirubin measurements. These may provide a strategy, in the future, for reliable office and home bilirubin assessments. However, the systems that are now available seem limited in their usefulness because they must be calibrated to a given laboratory, as well as calibrated for different skin types and colors.9
Although the major foci of research on neonatal jaundice have been toxicity and treatment, accurate and rapid measurement of elevated bilirubin concentration has also intrigued investigators. The standard clinical management of infants with jaundice includes visual estimates of the extent and serial estimation of serum bilirubin concentration by laboratory techniques using blood obtained by repetitive venous, arterial, or capillary puncture. Any mode of obtaining blood is a source of discomfort and infection. Transcutaneous bilirubinometry is a noninvasive and cost-effective alternative.
The practice of noninvasive bilirubin measurement in newborns predates our recognition of bilirubin as the agent responsible for jaundice. The device most commonly used is the human eye, with or without the aid of a reference device or a hand-held battery-powered meter. Simple visual estimates for the presence or absence of jaundice are made daily by pediatricians to aid in the decision to test serum bilirubin levels. The visual estimate is redefined by classifying the dermal zone of jaundice based on the phenomenon of cephalocaudal progression.
Jaundice in zone one (from head to neck and the level of the clavicle) translates approximately to a serum bilirubin concentration of 5 mg/dl; in zone two (from the clavicle to the umbilicus), to 6 – 8 mg/dl; in zone three (from the umbilicus to the knees), 9 – 12 mg/dl; in zone four (from the knees to the ankles), to 13 – 15 mg/dl; and in zone five (the palms and soles), to over 15 mg/dl. A second refinement of the visual estimate is the use of a reference device. In 1925 Rowntree and Brown used a tintometer, while in 1960, Gosset described the use of the Ingram Icterometer to gauge the depth of jaundice in newborns.
Jaundice needing treatment is generally calculated based on the amount of bilirubin and the age of the infant. A calculator, like the one available on www.bilitool.org, can calculate the infant's risk.10
A more sophisticated device is the Minolta/Air Shields Jaundice Meter. It works via the principle of skin reflectance, which assumes that subcutaneous bilirubin is correlated linearly to serum bilirubin. The ability to estimate serum bilirubin values can be simplified by using the compartmental model. The relationship between bilirubin concentrations in the subcutaneous tissue compartment and the blood compartment is governed by rate constants that describe the rate of entry and exit of bilirubin from one compartment to another.
To obtain a satisfactory correlation between these two values, the serum bilirubin measurements and the cutaneous bilirubin measurement must be accurate. The two compartments and the kinetics of the transfer of bilirubin to and from each compartment must be similar for every infant.
In studies of jaundice meters' precision, several investigators have found them less precise for low serum bilirubin levels. Still, others have suggested that the jaundice meter's accuracy may be compromised at higher serum bilirubin concentrations. Accuracy may also be compromised by the variability of individual meters, the influence of operator technique, and the presence of alcohol on the meter probe or the baby's skin. The accuracy of jaundice meters is a function of precision and the presence or absence of bias in the form of additional or interfering race-dependent skin chromogens and the presence of bruising or birthmarks. Factors such as exchange transfusion, phototherapy, body site measurement, albumin concentration, pH, and gestational and chronological age can alter results.
To avoid some of the know problems with transcutaneous devices, computerized photo-sensors that take advantage of skin tone information are being tested. Instead of registering the simple change in skin color caused by bilirubin, the meter can measure minute alterations in any one of a vast array of human skin types. This patient-specific analysis takes account of race and skin perfusion and, in effect, allows the computer to detect bilirubin below the surface.11
Surprisingly, phototherapy does not seem to interfere with the measurement, even though infants, while being treated, appear less jaundiced to the eye. The value of screening tools ultimately rests on the clinician's need to measure bilirubin in the newborn. The trends toward extremely early discharge after delivery, cost containment, and decreases in medical interventions should increase our requirements for simple safe methods of determining which infants have more than just physiologic jaundice.
Initially, bilirubin is transported in the plasma bound to albumin at two sites:
When available albumin-binding sites are saturated, bilirubin then circulates freely in the plasma. This portion of unconjugated bilirubin can migrate into brain cells, causing damage known as kernicterus. Kernicterus is the presence of yellow pigment in the brain (basal ganglia). This may result in encephalopathy and permanent brain damage.
Unconjugated bilirubin is toxic to the CNS. Kernicterus was originally a term describing the brain's typical autopsy findings in infants who died during severe jaundice, often caused by Rh isoimmunization or by infection. The term bilirubin encephalopathy is, in fact, more appropriate for the acute clinical findings.
The occurrence of kernicterus is related to the amount of diffusible, loosely bound bilirubin and albumin binding sites' availability. Free bilirubin easily crosses the blood-brain barrier and is transferred into the brain cells, causing obvious yellow staining of the brain tissue, similar to its effect on the skin. The brain's areas usually affected by the staining are the hypothalamus, dentate nucleus, and cerebellum. Kernicterus is associated with varying degrees of neurological damage, but a direct correlation between serum bilirubin levels and the severity of involvement cannot be drawn.5
Hyperbilirubinemia in full-term infants has become an uncommon event in the last 30 years due to recognizing an early prenatal intervention in Rh-negative mothers and the widespread use of Rho (D) immune globulin (RhoGAM), exchange transfusions, and phototherapy. After 1970, postmortem findings consistent with kernicterus were described in a new population of babies. With the improved survival of low-birth-weight (under 1500 grams) infants, pathologic changes were described even in the presence of low bilirubin levels and without the typical symptoms.
Early discharge has contributed to increased incidences of kernicterus. The American Academy of Pediatrics (AAP) has recommended guidelines for the management of all infants. The AAP recommends that a healthcare professional should evaluate all infants discharged prior to 48 hours of age within 48 hours after discharge. Education of healthcare professionals regarding kernicterus has become a priority for the AAP.
Many factors can influence the bilirubin-binding capacity and increase the risk of kernicterus at lower bilirubin levels. Some of those factors include:
Premature infants normally experience relative hypoproteinemia and have fewer albumin-binding sites available for free bilirubin. Certain drugs, such as sulfisoxazole and salicylates, compete with bilirubin for binding sites or replace bilirubin loosely attached to binding sites. Acidosis and hypoxia increase hydrogen ions' production, and implementation of anaerobic metabolism can impede bilirubin binding. Albumin's ability to bind bilirubin drops to one-half of its potential at a serum pH of 7.1, with free fatty acids, produced during anaerobic metabolism, competing for albumin-binding sites. When acidosis and hypoxia, which can open the blood-brain barrier, are concurrently present in a sick infant, said infant could be exposed to kernicterus at much lower serum levels. Evidence also suggests that subsequent CNS abnormalities are better correlated with test evaluating bilirubin-binding capacity rather than serum bilirubin concentrations.
Clinical Manifestations of kernicterus are as follows:
|Early Signs||Late Signs|
|Hypotonia||Tooth enamel abnormalities|
|Paralysis of upward gaze||High-pitched cry|
|Poor eating||Serum bilirubin levels are 30 mg/dl or greater (in term infants)|
The AAP's new guidelines provide reasonable criteria for when and how to start workups, when phototherapy should be started, and when exchange transfusions should be performed. When jaundice is initially noticed, the first step in the decision-making process is to determine whether it is pathologic or not. Most jaundice in infants is not pathologic, but one must carefully consider and exclude pathologic conditions before relaxing vigilance. Jaundice visible in the first 24 hours of life is generally considered pathologic.
Carefully review family and clinical history and physical findings for:
As stated earlier, pathologic jaundice is clinical jaundice at less than 24 hours of age, or bilirubin rising at greater than 0.5 mg/dl/hr, or true hemolysis. Any infant noted to be jaundiced during the first 24 hours of life should have a total serum bilirubin level determined. If the level is greater than 7 – 8 mg/dl during the first 24 hours of life, further laboratory workup, close observation and evaluation, and possible therapy are warranted. Workup may also be warranted if lower levels are found at an earlier age (such as 5 mg/dl at 8 hours of age).3
The workup may include some or all of the following:
If data suggests a rapidly rising bilirubin level (more than 0.5 mg/dl/hr) with or without evidence of hemolysis, then phototherapy is indicated. Because of the close in-hospital follow-up that these infants require, a neonatology consult may be helpful. These infants should be or remain hospitalized under phototherapy until bilirubin levels stabilize at a safe level based on the infant's age and whether the infant is full-term or preterm.
The presence of true hemolysis due to ABO incompatibility is indicated by a low or falling Hct (<45) and an abnormal blood smear (3+ to 4+ spherocytes). If hemolysis is documented by blood smear and anemia, but the bilirubin is not rising more than 0.5 mg/dl/hr, in-hospital observation is still warranted, with repeat bilirubin measurements every four to six hours until a peak and then leveling off (plus or minus 1 mg/dl) is observed. Clinical experience suggests that true hemolytic disease is associated with higher peak TSB levels.3
The presence of documented hemolytic disease due to Coombs positive ABO incompatibility or other etiologies requires aggressive evaluation and therapy, and probably the use of phototherapy at lower levels. In clinical practice, the hyperbilirubinemia associated with hemolytic disease seems less responsive to phototherapy. For infants with true hemolysis, an exchange transfusion is indicated if bilirubin levels reach levels between 18 and 23 mg/dl in full-term infants and between 15 to 18 mg/dl in preterm infants.
If bilirubin levels start to approach those associated with kernicterus despite phototherapy, exchange transfusion may be necessary to protect the jaundiced infant's CNS status. Also, it is recommended for the rapidly rising bilirubin within the first 24 hours of life. The object of this procedure is to remove bilirubin and the antibody-coated RBCs from the newborn's circulation.
After a single-volume exchange, 75 percent of the newborn's RBC mass is removed; a double-volume exchange removes 85 to 90 percent of the cells. However, bilirubin removal is much less effective, with only 25 percent of the infant's total body bilirubin being removed during a double-volume exchange. This probably occurs because the major portion of bilirubin is in the extravascular compartment, an area not affected by the exchange of blood volume. Rebound in bilirubin levels occurs within one hour of the exchange, and they reach as much as 55 percent of the pre-exchange values. The following criteria are used to determine the need and timing of exchange transfusion, particularly for infants with erythroblastosis fetalis12:
Selection and preparation of blood products are aimed at decreasing antigen-antibody reaction, removing toxic substances, substituting a higher, more efficient circulating RBC, and preventing biochemical imbalances caused by blood products during the exchange transfusion. Blood should be as fresh as possible, preferably less than 48 hours old.
Most healthy infants over 24 hours of age with non-pathologic jaundice can be safely managed as outpatients. No other lab work beyond the type and Coombs is needed if the medical assessment is negative. Healthy full-term infants who meet guidelines to receive phototherapy can be easily managed at home, especially with the available fiber optic phototherapy blankets.
The AAP guidelines present several treatment options for jaundiced breastfed infants. Breast-feeding may be continued while providing phototherapy. Phototherapy can be provided at home if the infant is feeding well, is active, appears well, and the TSB is less than 20 – 22 mg/dl in term infants or less than 18 in preterm infants. Assessment by a home health nurse is critical for the outpatient approach to work, although some physicians may want to assess the infant in their office initially. The home health nurse should be able to:
Native bilirubin is relatively insoluble in water at physiologic pH, but it is very lipid-soluble. Bilirubin is made more water-soluble in the liver by conjugation with glucuronic acid to produce conjugated or direct-reacting bilirubin. This is then cleared through the bile into the intestines and out through the feces. Phototherapy bypasses the hepatic system by producing photo isomers of bilirubin that are more water-soluble and can be cleared directly in bile or urine without conjugation in the liver.
When bilirubin absorbs a photon of light, one of three possible photochemical reactions can occur photo-oxidation, configurational isomerization, and structural isomerization. Photo-oxidation results in the formation of colorless water-soluble molecules. Although originally thought to be the main pathway of bilirubin elimination during phototherapy, the reaction now appears to occur too slowly to be of clinical importance. Configurational isomerization is the conversion of the bilirubin molecule to a more water-soluble form. Although this molecule's formation is the most rapid of the photochemical reactions, this molecule is excreted slowly, if at all. Structural isomerization produces lumirubin, a molecule that is formed relatively slowly but appears to be excreted fairly efficiently; it is thought to account for most or all of the pigment elimination during phototherapy. Lumirubin has been identified as the major bilirubin species in urine and aspirates of duodenal bile in infants undergoing phototherapy.
Phototherapy is also thought to enhance the hepatic excretion of unconjugated bilirubin and to increase bowel transit time. With early phototherapy initiation, a 20 to 35 percent reduction in serum bilirubin concentrations is noted by the second day of life, with a reduction of 41 to 55 percent by day four. This reduction is more significant than the naturally occurring drop in the untreated infant.
The color of light used in phototherapy is critical for its therapeutic success. As a yellow pigment, bilirubin can only absorb in the blue, violet, and green spectra. Irradiance is measured in microwatts per centimeter squared in nanometers. Irradiance and not the intensity of the light source are critical in successful management. 450 nm (nanometer) blue light is best absorbed, but the light of longer wavelengths, such as green light, is thought to penetrate infant skin more deeply.4 In addition to the appropriate wavelength, effective illumination must also be maintained. Spectroradiometer readings of 4 to 6 µW/cm2/nm are considered in the effective therapeutic range. Phototherapy units should be checked for adequate light levels with a radiometer before phototherapy is initiated and every eight to twelve hours while the lights are in use. The optimal distance between the light source and the infant is less than twenty inches.
Phototherapy may be stopped in a healthy term infant over one day of age when the bilirubin level falls 25-50 µmol/L (1.5-3 mg/dL) below the level that triggered the initiation of phototherapy. Serum bilirubin levels may rebound after treatment has been discontinued, and follow-up tests should be obtained within 6-12 hours after discontinuation.4 A rebound increase in the bili level of 1 mg/dl is normal. In healthy preterm infants over five to six days of age, phototherapy may be stopped when the TSB reaches 12 mg/dl or less. In a preterm less than five days old, phototherapy may be stopped cautiously at a TSB of 10 mg/dl, remembering that close follow-up is needed until after the predicting peaking of bilirubin at five to seven days of life. If levels do not respond by stabilizing or declining, then hospitalization and intensive phototherapy is warranted.
Fiberoptic light is also used in phototherapy units. These units deliver high energy levels but comparable to that of conventional low-output overhead phototherapy units. Drawbacks to fiberoptic phototherapy units include noise from the fan in the light source and damage or breakage of the optic fibers. Advantages include:
Because the effects of prolonged exposure to phototherapy lights can potentially cause retinal damage, infants undergoing phototherapy require eye protection. Phototherapy units and eye protection should be periodically removed throughout the day to provide the infant with visual stimulation and interaction with parents and caregivers.
Infants undergoing phototherapy require temperature stabilization appropriate for their size and overall condition. Adequate fluid intake and compensatory fluid adjustment for increased insensible water loss may be required to prevent dehydration in these infants. The infant under phototherapy will still need to have periodic monitoring of bilirubin levels to check therapy effectiveness. Because phototherapy lights can alter blood bilirubin results, the lights should be turned off during blood drawing for serum bilirubin determinations.
In general, phototherapy has no significant toxicity, and its side effects are few and are reversible with removal of the lights; they include:
Jaundice is one of the most common problems seen in the newborn. All infants need to be assessed for risk factors that may make an infant likely to develop pathologic jaundice. Parents must be educated on the significance of early identification and treatment to prevent the serious complication of kernicterus.
A nine-day-old boy was admitted to the pediatrics unit of a regional hospital after a newborn check-up, where he was found to be jaundiced with total serum bilirubin of 400 μmol/L. The public health nurse had followed him in the community for poor weight gain in his first week of life. His weight on admission was 2.52 kg, while his birth weight had been 2.81 kg.
Breastfeeding had been established before discharge home on the second day of life. It was supplemented with formula by bottle after an appointment on the fifth day at the pediatrician, where the boy was found to have lost over 10% of his birth weight. His parents reported that he was becoming less and less interested in eating, and by the day of admission, they needed to wake him for most feeds.
On admission, he was jaundiced and moderately dehydrated but otherwise had a normal physical examination. Other than the hyperbilirubinemia, the remainder of the initial blood work was unremarkable. The direct antiglobulin test was negative. The baby was started on double phototherapy and intravenous rehydration, and within six h, he had a repeat total bilirubin of 309 μmol/L, with a direct bilirubin of 34 μmol/L. A glucose meter check also performed at the time showed a reading of 26 mmol/L. A serum sample sent to the laboratory showed the glucose to be two mmol/L. Repeat glucose meter checks performed overnight were all greater than 20 mmol/L, while laboratory samples were in the low to normal range. After approximately 24 h of phototherapy, the total bilirubin was 250 μmol/L, with a direct bilirubin of 39 μmol/L. The baby developed a bronzed color (direct hyperbilirubinemia), and liver function tests showed an alkaline phosphatase of 685 U/L, alanine aminotransferase of 83 U/L, and aspartate aminotransferase of 155 U/L. A urine test result was able to point to the likely diagnosis quickly.
The urine was strongly positive for reducing substances and negative for glucose. Other studies performed as part of the direct hyperbilirubinemia evaluation included abdominal ultrasound (to assess liver and biliary anatomy), alpha-1-antitrypsin level; urine for viral culture; thyroid function; metabolic screen; and hepatitis viral serology. A confirmatory red blood cell study of galactose-1-phosphate uridyl transferase (GALT) activity showed markedly reduced quantity. The baby was started on a lactose-free soy formula two days after admission, resulting in a marked improvement in feeding, growth, and liver function tests.
Initial investigations should confirm a cholestatic picture, establish the liver function, and detect readily treatable disorders. Secondary investigations should identify a specific diagnosis among the more common etiologies.
Galactosemia is an autosomal recessive disorder in which galactose is not properly metabolized. Dietary lactose is broken down by lactase into glucose and galactose, and then, in a three-step process, galactose is converted to glucose. This metabolic pathway is particularly important for the newborn, whose main carbohydrate source is lactose. Classic Galactosemia, by far the most common variant, involves a deficiency of GALT. This results in a buildup of galactose-1-phosphate and other precursors, causing damage to many organs, including the liver, spleen, kidney, ocular lens, cardiac muscle, brain, gonadal tissue, and erythrocytes. The earlier the disorder is diagnosed and a galactose-free diet is implemented, the less damage will ensue.